Cancer is a multi-step process caused by genetic abnormalities in proto-oncogenes and tumor suppressor genes. A specific and effective form of cancer therapy may be to target the repair, replacement or inactivation of oncogenes. The ability of oncogene activation to induce tumorigenesis and inactivation to induce tumor regression are likely to depend on many parameters including the constellation of genetic events, epigenetic factors, as well as host factors such as immune mechanisms. Previously, we have demonstrated that oncogene-induced tumorigenesis is reversible utilizing conditional transgenic model systems that employ the Tet system. We have developed transgenic models in which we can conditionally regulate MYC, RAS and/or BCL2 oncogenes. Now, we will employ these models systems to examine how genetic context and host immune status influences the ability of oncogene activation to induce tumorigenesis and inactivation to reverse tumorigenesis. A key difficulty in interrogating these processes is the inability to directly follow specific pre-neoplastic and neoplastic subsets of cells within the context of a living subject. Similarly, it would be desirable to examine the consequences of the inactivation of specific oncogenic events within an established tumor. Logistically, it is impossible to perform a kinetic analysis of tumorigenesis through the examination of the multitude of mice required. Analytically, it is not possible to examine the precise consequences of oncogene activation and inactivation ex vivo - the ability to examine specific biologic outcomes in situ permits the evaluation of host context. The use of combined imaging including Bioluminescence Imaging (BLI), microPET and Flow Cytometry simultaneously will permit us to interrogate effects on multiple biological outcomes such as proliferative expansion, apoptosis, and intracellular signaling. Preliminary results will be presented that demonstrate that BLI provides a unique and powerful approach to gain new insight into how and to what extent the activation of oncogenes can induce tumorigenesis, as well as how oncogene inactivation induces the regression of hematopoietic tumors. We now propose to utilize BLI to analyze the kinetics of tumor regression upon MYC inactivation, in conjunction with microPET to analyze angiogenesis and phosphorylation state of MYC and phosphoprotein FACS analysis to examine associated changes in phosphoprotein expression. Through multi-modality imaging, we will gain insight into the mechanisms by which oncogenes initiate and sustain tumorigenesis that will serve as important clues towards the development of therapies that target oncogenes for the treatment of cancer.